Doripenem - A New Broad-Spectrum Carabapenem Antibiotic

Initially under development in the US by Peninsula Pharmaceuticals Inc., doripenem is now part of Johnson & Johnson's anti-infective R&D portfolio following its acquisition of Peninsula Pharmaceuticals in 2005. A new member of the carbapenem class of ß-lactam antibiotics, doripenem is indicated for the treatment of serious bacterial infections in hospitalised patients.

Marketed under the brand name Doribax in Europe and the US, it is an approved treatment for complicated intra-abdominal and complicated urinary tract infections, including pyelonephritis in adults.

In Europe it is also licensed for treatment of nosocomial pneumonia, including ventilator-associated pneumonia. In the US, however, the FDA has requested additional information before it will sanction approval of Doribax for this additional indication. The final approval for Doribax in Europe for complicated intra-abdominal infections (cIAI), complicated urinary tract infections (cUTI) and nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP) is yet to be obtained.

Meanwhile, in Japan, Shionogi, the drug's originator, markets doripenem under the brand name Finibax. Peninsula Pharmaceuticals acquired development and marketing rights to doripenem in the US in a licensing agreement signed with Shionogi in 2003. In the US Doribax is marketed by Ortho-McNeil-Janssen Pharmaceuticals.

At a time of rising rates of bacterial resistance to commonly used antibiotics, new agents are urgently needed to treat bacterial infections effectively and halt the spread of resistant strains.

This need is arguably greatest in the hospital environment, especially in intensive care units, where rates of antibiotic resistance are highest.

Broad-spectrum antibacterial activity

First introduced into clinical practice about 20 years ago, the carbapenems are the most recent addition to the ß-lactam class of antibiotics, one of the largest classes of antibiotics that also includes penicillins and cephalosporins.

Carbapenems share the broad-spectrum activity of the ß-lactam class but differ from earlier class members in possessing stability to most clinically important bacterial ß-lactamases. This makes them useful in first-line treatment of serious bacterial infections and as reserved therapy for defined resistant pathogens.

Doripenem, a 1-ß-methyl carbapenem, has a number of features that suggest it could be a useful addition to the current range of carbapenems:

• Enhanced activity against non-fermentative gram-negative bacilli
• Bactericidal activity against most pathogens
• Stability to human renal dehydropeptidases
• Stability to common bacterial ß-lactamases, including extended-spectrum ß-lactamases (ESBLs)
• Post-antibiotic effects against Pseudomonas aeruginosa
• Potent activity against penicillin-resistant streptococci
• Effective at low doses

Pivotal phase III trials

Based on results from successfully completed phase II trials conducted by Peninsula Pharmaceuticals, doripenem entered phase III development in the US. Regulatory approval was secured on the basis of four phase III trials which enrolled patients with complicated intra-abdominal and urinary tract infections. Across the four trials, doripenem emerged non-inferior to both meropenem and intravenous levofloxacin in complicated intra-abdominal and urinary tract infections. It was also well tolerated.

In pseudomonal eradication, doripenem was proved superior compared to meropenem. In two cIAI clinical studies conducted, doripenem cured 95% and 76% of patients respectively while meropenem cured only 79% and 69% respectively.

IV doripenem is also being evaluated in nosocomial pneumonia, which is among the most common infections in intensive care units accounting for about 15% of all hospital-acquired infections. Mortality exceeds 30% and is highest among mechanically ventilated patients. Selecting the right antibiotic is an important determinant of clinical outcome in such cases.

In the Japanese phase III trials, which formed the basis of regulatory submissions to the Japanese Ministry of Health, Labor and Welfare, IV doripenem was evaluated in pneumonia, chronic respiratory tract infections, and UTI.

Doripenem expands J&J's anti-infective portfolio

In addition to ofloxacn (Floxin) and levofloxacin (Levaquin), J&J has now added doripenem (Doribax) to its range of marketed antibiotics, while it awaits a decision from the FDA on ceftobiprole, in-licensed from Basilea Pharmaceutica AG.

Both doripenem (Doribax) and ceftobiprole are indicated for the treatment of serious bacterial infections in hospitalised patients. Although the hospital antibacterial market represents only a third of all antibacterial sales, increasing antibiotic resistance in the hospital environment has increased the demand for more effective antibiotics, making it an attractive sector for new antibacterial agents.

Marketing commentary

The past decade has seen a dramatic rise in antibiotic resistance in the hospital setting, compromising treatment outcome in critically ill patients. Of all the ß-lactam antibiotics, the carbapenems are considered to have the broadest spectrum of activity that includes coverage of non-fermentative gram-negative bacilli such as Acinetobacter spp and Pseudomonas aeruginosa. This makes them attractive agents for empirical therapy in the hospital setting against difficult-to-treat pathogens.